Associate editor: D. HoyerNicotinic acetylcholine receptors: From basic science to therapeutics
Section snippets
Introduction, brief history of nicotine and nicotinic acetylcholine receptors
As in the Sisyphean myth it might seem as if obtaining more knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) brings us first one step closer to the top of the knowledge hill before rolling back to see only more questions remaining. Progress made during the past twenty years has charted a course marked by the discovery of genes encoding nAChRs, by a better grasp of their pharmacology and by the identification of the receptors associated with neurological diseases. However, at the
Structure of neuronal nicotinic acetylcholine receptors: from genes to proteins
The isolation and purification of the protein corresponding to the muscle nAChR from the Torpedo electric organ by Jean-Pierre Changeux allowed a first reading of the corresponding amino acid sequence (Changeux et al., 1970). At the same time, spectacular progress in the field of molecular biology made it possible to identify and clone the gene encoding for the α subunit of the muscle receptor (Noda et al., 1983). Soon thereafter, the five genes encoding for the α1, β1, γ, δ and ε subunits were
Receptor distribution, genetics and disease
To appreciate the physiological role of nAChRs it is of crucial importance to have a thorough knowledge of both their macroscopic distribution, i.e. where subtypes are expressed in the nervous system, in tissues and organs, and their microscopic, subcellular distribution. In addition, the receptor distribution is important for understanding the relationship between receptor dysfunction and nervous system disorders.
Function and biophysical properties
Like all cell-surface ligand-gated ion channels, nAChRs modulate the flow of ions across the cell membrane and are under the control of an extracellular signaling molecule. A net influx of cations through the associated channel pore depolarizes the cell membrane and increases neuronal excitability. Calcium entry through some nAChRs produces additional effects on an array of intracellular signaling cascades. ACh, the natural endogenous ligand of nAChRs, is released from presynaptic cholinergic
Neuronal nicotinic acetylcholine receptor ligands in the clinic and in development
Nicotinic compounds that have shown promise as therapeutic agents are discussed below by the disease they target and are listed in Table 2 according to their development status. Compounds that have been discontinued for one or more indications are also included, since these may provide important clues as to why nicotinic drugs have failed for a certain indication. The bold numbers in brackets after a compound in the text below refer to the compound numbers in Table 2.
Selected preclinical and
The future of neuronal nicotinic acetylcholine receptor pharmacology and nicotinic drugs
Discoveries in the field of nAChRs have led to a step-wise progress in our understanding of these ligand gated ion channels, from the discovery of genes encoding for nAChRs, the identification of their physiological effects in the central nervous system, to the identification of gene associated diseases. These findings raised hope that new therapeutic avenues could be discovered that would result in the development of molecules targeting a wide range of disorders, from pain to cognitive
Conflict of interest statements
All authors declare that this review was prepared without external support. Daniel Bertrand and Hans Rollema have received payments as consultants for Pfizer Inc. Raymond Hurst is an employee of Pfizer Worldwide Research & Development.
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